This is a 371 of PCT/US93/03389filed Apr. 14, 1993.
The present invention relates to novel substituted benzothiazepines and benzoxazepines, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of central nervous system and gastrointestinal disorders. The pharmaceutically active compounds of this invention are cholecystokinin (CCK) receptor antagonists.
Cholecystokinin (CCK) is a 33-amino acid peptide originally discovered and characterized in 1971. (See Mutt et al., Biochem. J., 125, 57 (1971 )). It carries out its biological responses by binding to its two receptor types: CCK-A and CCK-B. The CCK-A receptor is located primarily in the gallbladder and pancreas, and mediates CCK-induced enzyme secretion and gallbladder contraction during a meal. The CCK-B receptor is located in the stomach, where it is involved in acid secretion, and in the brain, where it mediates pain and anxiety responses.
A number of potent and selective non-peptide antagonists for these two receptors are known (See M. G. Bock, Drugs of the Future, 16(7), 631-640 (1991) and R. M. Freidinger, Med. Res. Rev., 9, 271-290 (1989)). Merck's L-364,718 (devazepide) is a selective CCK-A antagonist. (See O'Neill et al., Brain Res., 534, 287-290 (1990)). Merck's benzodiazepine L-365,260 is a selective CCK-B antagonist that was found to have an analgesic effect on squirrel monkeys. (See O'Neill et al., Brain Res., 534, 287-290 (1990)). Parke-Davis' CI-988 is a selective CCK-B antagonist that was found to reverse the pentagastrin-induced anxiogenic response in rats. (See Singh et al., Proc. Nat'l. Acad. Sci., U.S., 88, 1130-33 (1991 )). U.S. patent application 825,677, filed Jan. 27, 1992, refers to substituted hexahydroazepinones and tetrahydrobenzazepinones that are selective CCK-B receptor antagonists.